All urologists have faced patients suffering a renal cancer asking for the occurrence of the disease in their offspring and very often the answer to this question has not been well founded from the scientific point of view, and only in few cases a familial segregation tree is performed. The grate shift seen in the detection of small renal masses and renal cancer in the last decades will prompt us to know the indications for familial studies, which and when are necessary, and probably to refer those patients with a suspected familial syndrome to specialized oncological centers where the appropriate molecular and familial studies could be done. Use of molecular genetic testing for early identification of at-risk family members improves diagnostic certainty and would reduce costly screening procedures in at-risk members who have not inherited disease-causing mutations. This review will focus on the molecular bases of familial syndromes associated with small renal masses and the indications of familial studies in at-risk family members.
Renal cell carcinoma
(RCC) affects approximately 150 000 people worldwide each year, causing close to 78 000 deaths annually, and its incidence seems to be
rising [
Classification of renal epithelial tumors.
Histological type | Frequency | Cell of origin | Behavior | Gene involved | Chromosomal abnormalities |
---|---|---|---|---|---|
Conventional (clear-cell) renal-cell carcinoma | 75% | Proximal renal tubule | Malignant | −3p, +5q, −Y, −8p, −9p, −14q; | |
t(3;5)(p;q) | |||||
Papillary renal-cell carcinoma | 10–15% | Proximal renal tubule | Malignant | +7, +17, −Y, +12, +16, +20; | |
t(X;1)(p11.2;q21.2), | |||||
t(X;17)(p11.2;q25.3) | |||||
Chromophobe renal carcinoma | 5% | Intercalated cell of renal collecting duct | Rarely malignant | −1, −2, −6, −10, −13, −17, −21 | |
Oncocytoma | 5% | Intercalated cell of renal collecting duct | Benign | −1, −Y; t(5;11)(q35;q13), | |
t(9;11)(p23;q13) | |||||
Collecting-duct carcinoma | 2% | Renal collecting duct | Aggressively malignant | −1p32, −6p, −8p, −21q |
Most cases of RCC are
thought to be sporadic whereas there has been estimated that hereditary RCC
syndromes are estimated at 1–4% but have major
clinical and scientific implications [
Hereditary renal cell carcinoma (RCC) syndromes and histological subtypes.
Renal tumors | Manifestation | Disease | Gene |
---|---|---|---|
Clear cell RCC | |||
Bilateral and multiple | Von Hippel-Lindau | ||
Bilateral and multiple | Chromosome 3 translocations | Unknown, | |
Hereditary paraganglioma | |||
Angiomyolipomas | Tuberous sclerosis | ||
Papillary RCC | Solid, bilateral and multiple (type 1) | Hereditary papillary RCC | |
Unilateral solitary, aggressive (type 2) | Hereditary leiomyomatosis | FH, 1q42-43 | |
Hamartomas, Wilm’s tumor | Hyperparathyroidism-jaw tumor | ||
Oncocytoma | Familial papillary thyroid cancer | ?, 1q21 | |
Chromophobe RCC | Oncocytic-chromophobe | Birt-Hogg-Dubé |
There are no generally accepted screening guidelines for hereditary RCC
syndromes; however, some recommendations can be made. A hereditary
predisposition to renal cancer should be suspected whenever an individual who
is diagnosed with renal cancer has a close relative also diagnosed with the
disease, and/or when an individual presents with multifocal renal tumors or a
history of previous renal tumor. Family history should be obtained and a
pedigree created, paying specific attention to relatives with a known history
of cancer. Whenever possible (when a gene-causing disease is identifiable), a
germline genetic testing should be performed on the proband. In addition, and
as a general rule, molecular genetic testing of at-risk family members is
appropriate in order to identify the need for continued, lifelong, clinical
surveillance. Interpretation of the result is most accurate when a disease-causing
mutation has been identified in an affected family member. Those who have a disease-causing mutation require lifelong regular
surveillance. Meanwhile, family members who have not inherited the mutation and their offspring have risks similar to the general
population [
In this case, and generally
speaking within a genetic testing context, the presence or absence of a
mutation in a predisposing gene or the type of mutation determines the clinical
actuation in cases of hereditary syndromes of cancer. In this sense, and
following the American College of Medical Genetics (ACMG) recommendations, we
can describe the following situations [
When the mutation is present:
the pathogenic sequence alteration is reported
in the literature; sequence alteration is predicted to be
pathogenic but not reported in the literature; sequence variation of unknown clinical
significance; sequence alteration is predicted to be benign
but not reported in the literature; a benign sequence alteration is reported in the
literature.
Possibilities if a sequence alteration is not detected:
patient does not have a mutation in the tested
gene (e.g., a sequence alteration exists in another gene at another locus); patient has a sequence alteration that cannot be
detected by sequence analysis (e.g., a large deletion, a splice site deletion); patient has a sequence alteration in a region of
the gene (e.g., an intron or regulatory region) not covered by the laboratory's
test.
Herein we review the four most frequent syndromes (von Hippel-Lindau, Hereditary papillary RCC, Hereditary leiomyomatosis RCC, and Birt-Hogg-Dubé), the molecular biology of the associated genes, and the clinical consequences of a genetic counseling.
VHL (OMIM: 193300) is
the main cause of inherited RCC [
Hereditary patterns and risks of renal cell carcinoma (RCC) associated syndromes.
Syndrome | Hereditary pattern | Risk of developing an RCC of the affected individuals |
---|---|---|
Autosomal dominant | 75% | |
Autosomal dominant | 20% | |
Autosomal dominant | 10–16% | |
Autosomal dominant | 15–29% |
Genetically, VHL is caused
by germline mutations in the
VHL disease tumor
suppressor protein (pVHL) has been implicated in a
variety of functions including transcriptional regulation, posttranscriptional gene expression, protein folding, extracellular matrix
formation, and ubiquitinylation [
Under normoxic
conditions, HIF1
VHL
complex interaction with HIF
However, under hypoxic
conditions, HIF1
Mutations in the
The molecular genetic
testing of
Over 300 different
Molecular genetic testing is indicated in all individuals
known to have or suspected of having VHL syndrome [
The level of mutation detection obtained by molecular genetic testing of the
Since pheochromocytoma
is part of the VHL syndrome spectrum and may occur as the exclusive
manifestation of VHL syndrome (type 2C),
individuals with a family history of these tumors, or those in whom
the disease is bilateral or multifocal, should be offered molecular genetic testing for
Use of molecular genetic testing for early identification of at-risk family members improves diagnostic certainty and
reduces the need for costly screening procedures in those at-risk family
members who have not inherited the disease-causing mutation [
Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions.
As mentioned above, VHL
syndrome is inherited in an autosomal dominant manner, and we call proband (or
index case) to the affected individual through whom a family
with a genetic disorder is ascertained. It has been reported that about 80% of
individuals diagnosed with VHL syndrome have an affected parent whereas de novo mutations of the
In the case of the sibs
of a proband, the risk of VHL syndrome to sibs depends upon the genetic status
of the parents: if a parent of a proband is clinically affected or has a disease-causing VHL mutation, the sibs of
the proband are at 50% risk of inheriting the altered gene; and if neither parent has the disease-causing VHL mutation identified in the proband, the sibs have a small risk of VHL syndrome because of
the possibility of germline mosaicism in one parent (at present the incidence of mosaicism
is not known) [
Each offspring of an affected individual has a 50% risk of
inheriting the mutant
Pedigree showing affected members with VHL.
Molecular genetic
testing of at-risk family members is appropriate in order to determine the need
for continued clinical surveillance. Interpretation of molecular genetic test
results is most accurate when a disease-causing germline mutation has been
identified in an affected family member. Those who have the disease-causing
mutation require regular surveillance, whereas family members who have not
inherited the disease-causing mutation and their offspring need have no
future concern [
Because early detection
of at-risk individuals affects medical management, testing of asymptomatic
individuals during childhood is beneficial [
The use of molecular genetic testing for determining the genetic status of presumably at-risk relatives when a family member with a clinical diagnosis of VHL syndrome is not available for testing is less straightforward. Such test results need to be interpreted with caution. A positive test result signals the presence of a VHL disease-causing mutation in the at-risk family member and indicates that the same molecular genetic testing method can be used to assess the genetic status of other at-risk family members. However, a negative test for a VHL gene mutation under such circumstances suggests one of the following possibilities:
the at-risk family member has not inherited a the familial the diagnosis of VHL syndrome in the affected family member is
questionable.
In this situation, the
presumably at-risk family member has a small, but finite, residual risk of
having inherited a disease-causing allele (i.e., VHL syndrome or other
hereditary disorder). In counseling such individuals, careful consideration
should be given to the strength of the clinical diagnosis of VHL syndrome in
the affected family member, the relationship of
the at-risk individual to the affected family member, the perceived risk
of an undetected
It is recommended that
physicians ordering
When neither parent of a proband with an autosomal dominant condition has the disease-causing mutation or clinical evidence of the disorder, it is likely that the proband has a de novo mutation. However, possible nonmedical explanations including alternate paternity or maternity (i.e., with assisted reproduction) or undisclosed adoption could also be carefully explored.
Hereditary papillary RCC
(HPRCC) (OMIM 605074) is characterized by the development of multifocal, bilateral
papillary type-1 RCCs (low-grade tumors with basophilic cells and a favorable
prognosis) occurring at a late age in
HPRCC is mainly caused
by activating germline mutations in the tyrosine kinase domain of the
Activating mutations in MET in HPRCC. (a) In normal cells, hepatocyte growth factor (HGF) binds to MET receptor to induce MET dimerization and release autoinhibition. This permits, through several phosphorilation steps, the activation of second-messenger molecules (such as GRB2, GAB1, or PI3K) leading to morphogenic, motogenic, and mitogenic programmes. (b) Renal cells from patients with HPRCC can harbour germline mutations in the tyrosine kinase domain of MET. These mutations release the autoinhibition by the MET carboxyl terminus, allowing the transition of the receptor to the active kinase form in absence of ligand stimulation.
Normal cell
HPRCC cell with
Tumors from patients with
papillary RCC and germline mutations of
The molecular genetic
testing of
Molecular genetic testing for a germline
There are no specific screening guidelines for families suspected of having HPRCC. Individuals in these families are encouraged to talk with their doctor about screening options for kidney cancer, including ultrasound, and CT scan. Some clinicians suggest that individuals who have HPRCC, or a family history that suggests HPRCC, should have yearly screening beginning at age 30.
Hereditary
leiomyomatosis renal cell cancer (HLRCC) (OMIM 605839) predisposes to multiple
cutaneous and uterine leiomyomas and solitary papillary type 2 RCCs [
The majority of
individuals (76%) present with a single or multiple cutaneous leiomyoma. These
lesions appear as skin-colored to light brown papules or nodules distributed
over the trunk and extremities, and occasionally on the face. Forty percent of
individuals with HLRCC have mild cutaneous manifestations with five or fewer
lesions [
Practically all females
with HLRCC develop uterine leiomyomas [
Most renal tumors are
unilateral and solitary. Approximately 10%–16% of
individuals with HLRCC who present with multiple cutaneous leiomyomas had renal
tumors at the time that renal imaging was performed [
The disease is caused by
germline mutations in the tumor suppressor gene
Activity of FH enzyme
can be measured in cultured skin fibroblasts or lymphoblastoid cells to confirm
the diagnosis. Reduced activity (≤60%) of FH enzyme was found in all affected individuals with the diagnosis of
HLRCC [
The overall risk for
renal tumor development is unclear and the mechanism of
Molecular genetic testing for a germline
multiple cutaneous leiomyomas (with at least one
histologically-confirmed leiomyoma) without a family history of HLRCC; a single cutaneous leiomyoma with family history of HLRCC; one or more tubulo-papillary, collecting-duct, or papillary type 2 renal
tumors with or without a family history of HLRCC.
Measurement of FH enzyme activity can be useful in the diagnosis of HLRCC in
cases with atypical presentation and undetectable
No correlation is
observed between
HLRCC is inherited in an
autosomal dominant manner. Some individuals diagnosed with HLRCC have an affected parent and some have HLRCC as the result of a de novo gene mutation. In this case, the proportion of cases caused by de novo mutations is unknown as subtle manifestation in parents has not
been evaluated and genetic testing data are insufficient. Recommendations for
evaluation of parents of a proband with a suspected de novo mutation include molecular genetic testing if the
In the case of the
siblings of a proband, the risk depends upon the genetic status of the
proband's parents. If a parent of a proband is clinically affected or has a disease-causing mutation, each sibling of the proband is at a 50% risk of inheriting the mutation. If the disease-causing mutation cannot be detected
in the DNA of either parent, the risk to siblings is low, but greater
than that of the general population because the possibility of germline mosaicism exists [
The risk to other family members depends upon the status of the proband's parents. If a parent is found to be affected or to have a disease-causing mutation, his or her family members are at risk.
It is not possible to predict whether symptoms will occur, or if they do, what the age of onset, severity, and type of symptoms, or rate of disease progression will be in individuals who have a disease-causing mutation.
When neither parent of a proband with an autosomal dominant condition has the disease-causing mutation or clinical evidence of the disorder, it is likely that the proband has a de novo mutation. However, possible nonmedical explanations including alternate paternity or undisclosed adoption could also be explored.
There is no consensus on
clinical surveillance for HLRCC individuals so far but the following provisional
recommendations have been accepted until a consensus conference is conducted [
Individuals with the clinical diagnosis of HLRCC, individuals with heterozygous mutations in FH without clinical manifestations, and at-risk family members who have not undergone molecular genetic testing should have the following regular surveillance by physicians familiar with the clinical manifestations of HLRCC.
Any suspicious renal lesion (indeterminate lesion, questionable or complex cysts) at a previous examination should be followed with a CT scan with and without contrast. PET-CT may be added to identify metabolically active lesions suggesting possible malignant growth. It must be taken into consideration that ultrasound examination alone is never sufficient.
Renal tumors should be evaluated by a urologic oncology surgeon familiar with the renal cancer of HLRCC.
Birt-Hogg-Dubé (BHD) syndrome (OMIM 135150) is a genodermatosis that
predisposes individuals to benign cutaneous lesions of the face and neck, spontaneous
recurrent pneumothorax and/or lung cysts, and renal tumors [
The disease is caused by
germline mutations in the
Molecular genetic testing is indicated in all individuals known to have or suspected of having BHD syndrome including individuals with the following.
Five or more facial or
truncal papules with at least one histologically confirmed fibrofolliculoma [ A family history of BHD syndrome with a single
fibrofolliculoma or a single renal tumor or history of spontaneous pneumothorax. Multiple and bilateral
chromophobe, oncocytic, and/or oncocytic hydrid renal tumors. A single oncocytic,
chromophobe, or oncocytic-hydrid tumor and a family history of renal cancer with any of the above
renal cell tumor types. A family history of autosomal dominant primary spontaneous pneumothorax
without a history of chronic obstructive
pulmonary disease.
Mutations in
Acquired mutations in
No correlation is observed between type of
BHD syndrome is
inherited in an autosomal dominant manner. Some individuals with BHD
syndrome have an affected parent and some have BHD syndrome
as a result of a de novo gene mutation. The proportion of cases caused by de
novo mutations is unknown as a sufficient number
of parents have not been evaluated for subtle manifestations, nor are there
sufficient data on clinically unaffected parents who have been evaluated by molecular genetic testing. Recommendations for the evaluation
of parents of a proband with a suspected de novo mutation include molecular genetic testing if the disease-causing mutation in
the
The risk to the siblings of the proband depends upon the genetic status of the proband's parents. If a parent of a proband is clinically affected or has a disease-causing mutation, the sibs of the proband are at a 50% risk of inheriting the mutation. If neither parent has the disease-causing mutation identified in the proband, the risk to sibs is low, but greater than that of the general population because the possibility of germline mosaicism exists.
When neither parent of a proband with an autosomal dominant condition has the disease-causing mutation or clinical evidence of the disorder, it is likely that the proband has a de novo mutation. However, other possible nonmedical explanations could also be explored.
There is no consensus on clinical surveillance; therefore, these recommendations are provisional until a consensus conference is conducted.
Individuals with known BHD
syndrome, individuals known to have disease-causing mutations in
if normal at baseline, abdominal/pelvic CT scan with contrast every two
years; if any suspicious lesion (indeterminate lesion, questionable or complex
cysts) at previous examination, annual abdominal/pelvic CT scan with contrast
alternating every other year with MRI to reduce lifetime exposure to radiation; evaluation of renal tumors by a urologic surgeon; monitoring of tumors less than three centimeters in diameter by periodic
imaging; they may not require surgical intervention while this small.
The identification of
genes responsible for inherited RCC has resulted in a better understanding of
renal tumorigenesis including sporadic RCC and is paving the way for new
therapeutic approaches [
Recent studies suggest
that HIF overexpression is involved in HLRCC tumorigenesis [
The study of families with increased rates of cancer will continue to yield more insight into the factors that increase cancer risk. Genetic predisposition in the form of mutations and polymorphisms will increasingly be catalogued and DNA-level genetic profiling of high-risk families and individuals will become commonplace. The increase in availability of genetic testing and counseling for high-risk families should prove both helpful and cost-effective, as genetically unaffected family members reassured regarding their health status and removed from lifelong follow-up screening programmes.
Finally, we also should
keep in mind, although not deeply discussed in this review, the psychological and
ethical implications of the genetic counseling [